A bare metal stent is an implantable material used for treatment purpose so as to increase a blood vessel diameter by being grafted at a disease site at which the blood vessel diameter is reduced caused by atherosclerotic plaque, neoplastic tissue, cruor, or the like, which blocks blood from flowing or allow the blood not to smoothly flow.
A disease in which this stent is mainly used is cardiovascular diseases, which account for 30% or more of causes of death in the world, and more than 17.5 million people have died every year due to these diseases. Ischemic cardiovascular diseases occupying the largest portion of the cardiovascular diseases as described above mean that problems (atherosclerotic plaque, neoplastic tissue, or cruor) are generated in a coronary artery supplying blood to heart muscle, and a method for treating ischemic heart disease is divided into a non-invasive method (drug therapy) and an invasive method (angioplasty). Among them, a bare metal stent used in conventional angioplasty, which is the invasive method, has an excellent treatment effect of enlarging a coronary artery diameter to fix the enlarged coronary artery diameter, but it was reported in academia and a clinical treatment field that restenosis occurring after the bare metal stent was grafted was the biggest problem.
A drug eluting stent (DES), which was developed in order to prevent restenosis as described above, significantly reduced a generation rate of restenosis in patents. However, in spite of incorporating the treatment using an anti-thrombotic agent (aspirin and clopidogrel), late thrombus formation that did not appear well in animal tests has appeared in patents after 3 or 5 years or more of the graft of the drug eluting stent. As the reason, a hypothesis that the drug eluting stent effectively inhibits proliferation or inflammation reactions of vascular smooth muscle cells but excessively inhibits growth of endothelial cells at the same time, and thus a re-endothelization process of covering a surface of the stent is delayed, which causes the late thrombus formation has been persuasively accepted until now.
For this reason, an effort to find an ideal method capable of not inhibiting growth of endothelial cells while inhibiting proliferation of vascular smooth muscle cells has been continuously made domestically and globally, but it is impossible to allow a drug used for the drug eluting stent to affect only a specific cell due to characteristics of a chemical material. Therefore, as an alternative, a treatment method using genes that may be relatively cell-specifically expressed has been suggested. In relation to this, various studies have been conducted domestically and globally, and as a result, a method of preparing a DNA controlled release stent by coating a surface of the stent using polylactic-polyglycolic acid (PLGA) and collagen-polylactic-polyglycolic acid together with each other among non-degradable polymers to discharge a GFP gene, which is a report gene, to the outside of the stent has been reported in 2000 (Gene Delivery from a DNA Controlled-Release Stent in Porcine Coronary Arteries, Bruce D. et al., NATURE BIOTECHNOLOGY, 2000, Vol. 18, 1181-1184; Bisphosphonate-Mediated Gene Vector Delivery from the Metal Surfaces of Stents, Ilia Fishbein et al., PNAS., 2006, Vol. 103, 159-164).
In addition, an effect of delivering iNOS genes to reduce formation of neointima by a method of coating a surface of a metal stent with polyalanine bisphosphonate (PAA-BP), which is an aqueous polymer, and then binding adenovirus thereto again using a binding agent was reported by Ilia Fishbein et al., in 2006, such that a possibility of inhibiting restenosis using the gene delivery stent was reported (DNA Delivery from an Intravascular Stent with a Denaturated Collagen-Polylactic-Polyglycolic Acid-Controlled Release Coating: Mechanisms of Enhanced Transfection, I Perlstein et al., Gene Therapy, 2003, Vol. 10, 1420-1428).
However, in most of the current technologies, in order to form a coating layer to which a gene complex may be bound on a surface of a metal so that the gene complex is adhered to a metal stent made of stainless steel, a non-degradable organic polymer or degradable collagen has been used, or in order to increase gene transfection efficiency, a viral vector has been used.
In the case of a technology of fabricating a gene eluting stent using the existing polymer, problems such as allergy, inflammation reactions, or the like, may be generated by the organic polymer, and it may be significantly difficult to find a polymer having excellent biocompatibility. In addition, in the case in which the stent is fabricated using the viral vector, it is still not free from a possibility of generating cancer and inducing immune reactions.
Therefore, introduction of another coating material for coating the gene complex has been demanded. Particularly, this coating layer should have an appropriate functional group to which the gene complex may be sufficiently bound, a uniform surface, and excellent biocompatibility such as an anti-thrombotic property, an anti-inflammatory property, and the like. In addition, only when a coated polymer layer has an excellent adhesive property with a substrate and excellent mechanical strength, the polymer thin film may endure a strong blood flow during a medical operation and disinfection process or after the medical operation for a long period of time.
Therefore, in order to increase a success rate of introducing the DNA Controlled-Release Stent, selection of a thin film material that does not have these problems and development of a coating technology thereof and a gene complex adhering technology are essentially demanded.